Project IV: Neuroendocrine Approaches to Anti-Cocaine Medications is part of a new application for a NIDA program project (POI) entitled Cocaine and Polydrug Abuse: New Medication Strategies: A series of seven preclinical studies are proposed to examine the effects of cocaine on anterior pituitary, gonadal and adrenal hormones. We hypothesize that the rapid hormonal changes induced by acute i.v. cocaine administration may contribute to its abuse-related effects. We also hypothesize that repeated stimulation of these hormones by cocaine may contribute to the menstrual cycle disruptions observed during chronic cocaine self-administration and withdrawal. The pharmacological mechanisms that mediate cocaine's acute endocrine effects observed in clinical studies in Project III will be examined in preclinical models must be used to ask questions about the mechanisms mediating cocaine's stimulation of the endocrine system. In addition, these preclinical endocrine studies will complement behavioral studies proposed in Projects II and V. Endocrine studies will be conducted in males and in females at the mid- follicular and mid-luteal phase to determine if there are significant gender or menstrual cycle phase related differences in cocaine's acute hormonal effects. Menstrual cycle phase will be verified by radioimmunoassay of gonadotropin and gonadal steroid hormones. Once the temporal profile of cocaine's acute effects has been determined, monoamine agonists and antagonists will be administered to examine the pharmacological mechanisms that mediate cocaine acute endocrine effects. Binge patterns of cocaine abuse are reported clinically but little is known about the endocrine effects of repeated cocaine doses. We propose to simulate a cocaine binge and determine if hormones usually stimulated by cocaine continue to increase, plateau, or eventually decrease when cocaine is administered every 15 or 30 minutes. The hormone profile of cocaine's cute effects will also be studied after chronic cocaine self-administration to determine if tolerance or sensitization occurs. The most effective anti-cocaine medications identified in Project II will be evaluated to determine if these alter the endocrine profile of cocaine alone. The effects of cocaine + heroin combinations of "speedballs" on anterior pituitary, gonadal and adrenal hormones are unknown. Endocrine studies of behaviorally relevant ratios of cocaine to heroin are proposed to complement behavioral studies of speedball combinations and anti- speedball medications in Project II. Taken together, these studies should clarify the interactions between the endocrine system and cocaine and cocaine+ heroin combinations. Findings from these inter-related studies should suggest novel approaches to the development of anti-cocaine medications.